1. Field of the Invention
Cardiac arrhythmias are disorders of impulse generation that result from disruptions of normal cardiac pacemaker activity, from disturbances in cardiac conductive fibers, or from a combination of both preceding factors. Cardiac arrhythmias of clinical significance in man include: premature contractions (extrasystoles) originating in atrial or ventricular foci; paroxysmal supraventricular tachycardia; atrial flutter; atrial fibrillation; ventricular tachycardia; and ventricular fibrillation. Arrhythmias can be induced to laboratory animals that are suitable experimental models of man to study physiological mechanisms of the disorder or to screen new antiarrhythmic agents.
Clinical treatment of arrhythmias includes administration of a variety of drugs, although quinidine, procainamide, and diphenylhydantoin are current mainstays.
Quinidine is the d-isomer of quinine: ##SPC2##
While procainamide is p-amino-N-(2-diethylaminoethyl)-benzamide: ##STR1## I and II require extreme care in administration because they are relatively toxic. In weighing their efficacy over their toxicity, however, the former is countervailing. Because of limitations in those antiarrhythmic drugs, there have been efforts to discover safer substitutes. The discovery of the antiarrhythmic activity of diphenylhydantoin opened new approaches in the design of new compounds exhibiting such activity.
Diphenylhydantoin (5,5-diphenyl-2,4-imidazolidinedione; "DPH"), ##SPC3##
initially was utilized in the treatment of epilepsy but later was discovered to have important antiarrhythmic applications. The pharmacodynamics of DPH differ from those of quinidine and of procainamide, and DPH does not exhibit the toxic properties of either drug. DPH specifically antagonizes ventricular arrhythmias induced by digitalis, depresses ventricular automaticity, enhances atrio-ventricular nodal conduction, and reduces the effective refractory period. DPH, however, is not without untoward side effects: dizziness, nausea, emesis, nystigmus, and ataxia. Large doses of DPH may produce atrio-ventricular blockage, bradycardia, or even cardiac arrest. For a review of the current status of the field and of DPH as an antiarrhythmic agent, see: G. K. Moe and J. A. Albildskow, "Antiarrhythmic Drugs", in: The Pharmacological Basis of Therapeutics, 4th Edition, L. S. Goodman and A. Gilman, Editors, MacMillan Company, New York, Chapter 32 (1970); and L. S. Dreifus and Y. Watanabe, Amer. Heart J., 80: 709-713 (1970).
2. Description of the Prior Art
Relevant to the present invention are the following references: H. Henze, U.S. Pat. No. 2,526,231 Oct. 17, 1950; "Henze"); and C. Casagrande et al., Il. Farmaco Ed. Sc., 29: 757 (1974; "Casagrande").
Henze discloses synthesis of 5-phenyl-5-pyridyl hydantoins having the common structure, ##SPC4##
in which R is a 2-pyridyl, 3-pyridyl, or 4-pyridyl group, by reaction of an appropriate arylpyridylketone with a system comprising an alkali-metal cyanide, ammonia, carbon dioxide, and water in an inert organic solvent at temperatures of 100.degree. to 150.degree. C in a reaction bomb. The Henze patent contains three specific examples of IV that are used as starting materials for the compounds of the present invention and as reference compounds for comparative pharmacological tests: 5-phenyl-5-(2-pyridyl)-hydantoin (V); 5-phenyl-5-(3-pyridyl)-hydantoin (VI); and 5-phenyl-5-(4-pyridyl)-hydantoin (VII). While Henze teaches that compounds IV-VII exhibit anti-convulsant activity and are useful in the treatment of epilepsy, it contains no express or implied disclosure relating to use of compounds IV-VII as antiarrythmic agents.
Casagrande describes certain 3-substituted-5-phenyl-5-pyridyl-hydantoin derivatives of the structural formula, ##SPC5## in which: R' is a 2-pyridyl, 3-pyridyl, or 4-pyridyl moiety; m is an integer having a value of 1 or 2; and R" is a dimethylamino, diethylamino, or piperidino group. The reference, however, discloses no compounds in which R" is a 4-phenyl-piperidino, 4-phenyl-4-hydroxy-piperidino, or 4-phenyl-4-alkoxy-piperidino substituent. Although Casagrande teaches that compounds VII exhibit antiarrhythmic activity, it discourages further investigation in 3-substituted-5-phenyl-5-pyridyl-hydantoin analogues. Casagrande reports that when substituent R" of VIII is piperidino, antiarrhythmic activity is diminished: "Other modifications, which resulted in lower activity, were as follows: . . . (b) substituting the piperidino for the dimethylamino group . . . " (Il Farmaco, Ed. Sc., 29: 757 at 775 [1974]; emphasis added). Casagrande also indicates that none of compounds VIII have a therapeutic index greater than that of quinidine: "Among the compounds examined, the .beta.-pyridyl derivatives [3-(2-dimethylamino-ethyl)-5-phenyl-5.beta.-pyridyl-hydantoin; compound XXV in Casagrande] and [3-(2-methyl- 3-dimethylamino-propyl)-5-phenyl-5.beta.-pyridyl-hydantoin; compound XXX in Casagrande] appeared to deserve further investigation . . . . However, on the basis of an overall appraisal of the pharmacological results, it was concluded that what we estimate to be the most important prerequisite of any improved antiarrhythmic agents [sic], i.e., a therapeutic index clearly superior to that of quinidine, had not been fulfilled either by compound XXV or XXX . . . (ibid. emphasis added)".
The compounds of the present invention are novel over the Henze and Casagrande references. Furthermore, Example 6 of this specification demonstrates that the claimed compounds are nonobvious in view of those references and provide technical advance in the field: they are very active notwithstanding the presence of a substituted piperidino moiety and exhibit therapeutic indices significantly superior to quinidine.